Delivery of ultra pure nitric oxide (NO)

ABSTRACT

A system for delivering a therapeutic amount of nitric oxide can include a reservoir containing a nitrogen dioxide source. A heating element can be configured to heat the reservoir, causing nitrogen dioxide vapor to exit the reservoir through a restrictor into a conduit. The nitrogen dioxide vapor can mix with gas from a gas supply, which can then flow to a cartridge that includes a surface-activated material saturated with an aqueous solution of a reducing agent. The cartridge can convert the nitrogen dioxide into nitric oxide.

CLAIM OF PRIORITY

This application is a continuation of U.S. application Ser. No.14/546,373, filed Nov. 18, 2014, now U.S. Pat. No. 10,179,222, which isa continuation of U.S. application Ser. No.: 13/094,535, filed Apr. 26,2011, now U.S. Pat. No. 8,887,720, which claims priority to U.S.Provisional Application No. 61/328,010, filed on Apr. 26, 2010, each ofwhich is incorporated by reference in its entirety.

TECHNICAL FIELD

This description relates to a systems and methods for the delivery ofultra pure nitric oxide.

BACKGROUND

Nitric oxide (NO), also known as nitrosyl radical, is a free radicalthat is an important signalling molecule. For example, NO can causesmooth muscles in blood vessels to relax, thereby resulting invasodilation and increased blood flow through the blood vessel. Theseeffects can be limited to small biological regions since NO can behighly reactive with a lifetime of a few seconds and can be quicklymetabolized in the body.

Some disorders or physiological conditions can be mediated by inhalationof nitric oxide. The use of low concentrations of inhaled nitric oxidecan prevent, reverse, or limit the progression of disorders which caninclude, but are not limited to, acute pulmonary vasoconstriction,traumatic injury, aspiration or inhalation injury, fat embolism in thelung, acidosis, inflammation of the lung, adult respiratory distresssyndrome, acute pulmonary edema, acute mountain sickness, post cardiacsurgery acute pulmonary hypertension, persistent pulmonary hypertensionof a newborn, perinatal aspiration syndrome, haline membrane disease,acute pulmonary thromboembolism, heparin-protamine reactions, sepsis,asthma and status asthmaticus or hypoxia. Nitric oxide can also be usedto treat chronic pulmonary hypertension, bronchopulmonary dysplasia,chronic pulmonary thromboembolism and idiopathic or primary pulmonaryhypertension or chronic hypoxia.

Generally, nitric oxide can be inhaled or otherwise delivered to theindividual's lungs. Providing a therapeutic dose of NO could treat apatient suffering from a disorder or physiological condition that can bemediated by inhalation of NO or supplement or minimize the need fortraditional treatments in such disorders or physiological conditions.Typically, the NO gas can be supplied in a bottled gaseous form dilutedin nitrogen gas (N₂). Great care should be taken to prevent the presenceof even trace amounts of oxygen (O₂) in the tank of NO gas because theNO, in the presence of O₂, can be oxidized to nitrogen dioxide (NO₂).Unlike NO, the part per million levels of NO₂ gas can be highly toxic ifinhaled and can form nitric and nitrous acid in the lungs.

SUMMARY

In one aspect, a system for delivering a therapeutic amount of nitricoxide can include a reservoir, a gas supply and a delivery conduit. Areservoir can be configured to include a nitrogen dioxide source. Adelivery conduit can include at least one cartridge. The at least onecartridge can include a surface-activated material and a reducing agent.

In another aspect, a reservoir assembly include a reservoir arestrictor.

In another aspect, a method of delivering nitric oxide can includereleasing nitrogen dioxide from a reservoir into a delivery conduit viaa restrictor, passing a gas from a gas supply into the delivery conduitwhich can allow the gas from the gas supply and the nitrogen dioxide tomix in the delivery conduit, passing the gas and nitrogen dioxidemixture through at least one cartridge, and delivering nitric oxide froman outlet of the delivery conduit.

In another aspect, a method of manufacturing a reservoir assembly fordelivering nitric oxide can include coupling a restrictor to thereservoir, sealing a second end of the restrictor. The method can alsoinclude filling a reservoir with a source of nitrogen dioxide. Filling areservoir can include filling a portion of the reservoir with a sourceof nitrogen dioxide. The method can further include inserting therestrictor into a metal tube that can be coupled to the reservoir via anadaptor, holding the restrictor place by graphite ferrules, heat sealingthe restrictor, and/or testing the restrictor and/or assembly with ahelium flow. The testing can be used to check for leaks prior to fillingwith liquid N₂O₄.

In some embodiments, a reservoir can include a nitrogen dioxide source.In some embodiments, the nitrogen dioxide source is dinitrogentetroxide, more specifically, dinitrogen tetroxide. The amount of liquidN₂O₄ in the reservoir can be less than about 5.0 g, less than about 2.0g, less than about 1.0 g, less than about 0.50 g, less than 0.25 g orless than 0.10 g; the amount of liquid N₂O₄ in the reservoir can begreater than about 0.05 g, greater than about 0.10 g, greater than about0.20 g, greater than about 0.50 g or greater than about 1.0 g. Theamount of liquid N₂O₄ in the reservoir can be less than about 5 ml, lessthan about 2 ml, less than about 1 ml, less than about 0.5 ml, less thanabout 0.25 ml or less than about 0.10 ml; the amount of liquid N₂O₄ inthe reservoir can be eater than about 0.001 ml, greater than about 0.01ml, greater than about 0.05, greater than about 0.10 ml, greater thanabout 0.25 ml, greater than about 0.50 ml or greater than about 1.0 ml.

In some embodiments, the reservoir can include a restrictor. In somecases, the restrictor can be coupled to the reservoir.

In some embodiments, a reservoir can also include nitrogen dioxide vaporor nitrogen dioxide gas in a space over the nitrogen dioxide source.

In some embodiments, a reservoir can be less than 6 inches, less than 4inches, less than 3 inches, less than 2 inches, less than 1 inch, lessthan 0.5 inch in height. A reservoir can also be less than 4 inches,less than 2 inches, less than 1 inch, less than 0.75 inch or less than0.5 inch in internal diameter.

In some embodiments, a restrictor can include an orifice.

In some embodiments, a restrictor can include a first end and a secondend. In some embodiments, the first end of the restrictor can be coupledto a reservoir. In some embodiments, the second end can be sealed orclosed. In some embodiments, the second end, which was previously sealedor closed, can be opened, unsealed or include a broken seal. In someembodiments, the second end of the restrictor can also be coupled to thedelivery conduit. In some embodiments, the delivery conduit can includea device for opening the second end or breaking the seal on the secondend.

In some embodiments, a restrictor can further include a lengthcorresponding to the distance between the first end and the second end.In some cases, the second end of the restrictor is coupled to thedelivery conduit such that the delivery conduit traverses in a directionperpendicular to the length of the restrictor.

In some embodiments, the restrictor can include a tube. In someembodiments, the tube can be a capillary tube, more specifically, aquartz capillary tube. In some embodiments, the length of the restrictorcan be at least about 0.1 inch, at least about 0.25 inch or at leastabout 0.5 inch; the length can be at most about 4 inches, at most about2 inches, at most about 1 inch, or at most about 0.5 inch. Preferably,the restrictor can have a length of about 0.75 inch. In someembodiments, the internal diameter of the restrictor can be at leastabout 0.001, at least about 0.005 microns or at least about 0.010; theinternal diameter can be at most about 0.100 microns, at most about0.050 microns, at most about 0.025 microns, or at most about 0.010microns. Preferably, the restrictor can have a diameter of about 0.010microns.

In some embodiments, the gas supply can supply air, oxygen or nitrogen.In some circumstances, the gas supply can be an air supply, morespecifically, an air pump. The air pump can be battery powered. The gassupplied by the gas supply can be moist or dry. In some embodiments, thegas supply can be in fluid communication with the delivery conduit.

In some embodiments, the delivery conduit can have an inlet coupled tothe gas source. In some embodiments, the delivery conduit can alsoinclude an outlet. In some circumstances, the delivery conduit caninclude an outlet coupled to the patient interface. A patient interfacecan include a mouth piece, nasal cannula, face mask, or fully-sealedface mask.

In some embodiments, a cartridge can include a surface-activatedmaterial and a reducing agent. In some cases, the surface-activatedmaterial can be saturated with an aqueous solution of a reducing agent.Any appropriate reducing agent that can convert NO₂ or N₂O₄ to NO can beused as determined by a person of skill in the art. For example, thereducing agent can include a hydroquinone, glutathione, and/or one ormore reduced metal salts such as Fe(II), Mo(VI), NaI, Ti(III) orCr(III), thiols, or NO₂ ⁻. The reducing agent can be an antioxidant. Theantioxidant can be an aqueous solution of an antioxidant. Theantioxidant can be ascorbic acid, alpha tocopherol, or gamma tocopherol.Any appropriate antioxidant can be used depending on the activities andproperties as determined by a person of skill in the art. Theantioxidant can be used dry or wet.

In some circumstances, the cartridge can also include an inlet and anoutlet. The inlet can be configured to receive a gas flow that caninclude nitrogen dioxide and can fluidly communicate the gas flow to theoutlet through the surface-active material, such that the surface-activematerial can react with nitrogen dioxide in the gas flow and can convertthe nitrogen dioxide to nitric oxide.

In some embodiments, the delivery conduit further can include a secondcartridge. The second cartridge can include a surface-activated materialand a reducing agent. In some circumstances, the cartridge can alsoinclude an inlet and an outlet. The inlet can be configured to receive agas flow that can include nitrogen dioxide and can fluidly communicatethe gas flow to the outlet through the surface-active material, suchthat the surface-active material can react with nitrogen dioxide in thegas flow and can convert the nitrogen dioxide to nitric oxide.

In some embodiments, the system can include a disposable module and abase unit. In some embodiments, the disposable module can include thereservoir, the restrictor and the first cartridge. In some embodiments,the system can include a base unit, where the base unit can include agas supply. In some embodiments, the base unit can include batteries,sensors and/or alarm electronics. In some embodiments, the base unit isreusable. In some embodiments, the disposable module can be attached tothe base unit for delivery nitric oxide. In some circumstances, thedisposable module is configured to be used or attached to the base unitonly once.

In some embodiments, the method can further include comprising attachinga disposable module including a reservoir, a restrictor and a firstcartridge to a base unit. The base unit can include the gas supply. Thebase unit can also include batteries, sensors and/or alarm electronics.

In some embodiments, a system can be portable. In some embodiments, aportable system can include a belt hook, belt, shoulder strap or otherdevice for attaching a portable system to a person.

In some embodiments, the system can weigh less than 64 ounces, less than32 ounces or less than 16 ounces. In some embodiments, the system can beless than 2 feet, less than 1.5 feet, less than 1 foot in height; thesystem can be less than 2 feet, less than 1.5 feet, less than 1 foot,less than 9 inches or less than 6 inches in width; and/or the system canbe less than 6 inches, less than 4 inches, less than 3 inches or lessthan 2 inches in depth.

In some embodiments, a reservoir assembly can be less than 1 foot, lessthan 6 inches, less than 5 inches, less than 4 inches, less than 3inches or less than 2 inches in height and/or less than 1 inch, lessthan 0.75 inch or less than 0.5 inch in diameter.

In some embodiments, the system can further include a nitric oxidesensor, a nitrogen dioxide sensor, a flow sensor, a pressure sensor, asensor for atmospheric pressure, and/or a microbial filter.

In some embodiments, a system can further include a heating element. Aheating element can include a hot water bath, a heating mantle, heatingwire or heating well. A heating element can include a simple flexiblecircuit board with the wires etched onto the surface. In some cases, adevice including a thermistor can be built into the circuit formeasuring and controlling the temperature.

In some embodiments, the system can operate at a temperature of at leastabout 25° C., at least about 30° C., at least about 35° C., at leastabout 40° C., at least about 45° C. or at least about 50° C.; the systemcan operate at a temperature of at most about 200° C., at most about150° C., at most about 100° C., or at most about 75° C. The optimumtemperature range can be about 45 to 75° C.

In some embodiments, a method of delivering nitric oxide can includebreaking the seal on or opening an end of the restrictor. Breaking theseal on or opening an end of the restrictor can allow nitrogen dioxideto traverse the length of the restrictor and out the previously closedor sealed end of the restrictor.

In some embodiments, a method of delivering nitric oxide can includeheating a reservoir and/or restrictor to a temperature at least about25° C., at least about 30° C., at least about 35° C., at least about 40°C., at least about 45° C. or at least about 50° C.; a method ofdelivering nitric oxide can include heating a reservoir and/orrestrictor to a temperature at most about 200° C., at most about 150°C., at most about 100° C., or at most about 75° C. The optimumtemperature range can be about 45 to 75° C. In some embodiments,releasing nitrogen dioxide from a reservoir into a restrictor and theninto a delivery conduit can include heating a reservoir and/orrestrictor. In some embodiments, heating a reservoir and/or restrictorcan beat nitrogen dioxide in the reservoir, increasing the vaporpressure and releasing the nitrogen dioxide from releasing nitrogendioxide from a reservoir into a restrictor and then into a deliveryconduit.

In some embodiments, a reservoir assembly can include a heating element,which can reach and maintain a temperature of at least about 25° C., atleast about 30° C., at least about 35° C., at least about 40° C., atleast about 45° C. or at least about 50° C.; a reservoir assembly caninclude a heating element, which can reach and maintain a temperature ofat most about 200° C., at most about 150° C., at most about 100° C., orat most about 75° C. The optimum temperature range can be about 45 to75° C. In some embodiments, a method of manufacturing a reservoirassembly can include attaching a heating element, where the heatingelement can reach and maintain the temperatures discussed above.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram of a gas bottle platform.

FIGS. 2A and 2B are diagrams of a cartridge.

FIG. 3 includes a diagram of a cartridge and a cut-away diagram of acartridge.

FIG. 4 is a diagram of a cap of a cartridge.

FIG. 5 is a diagram of a system for delivering nitric oxide.

FIG. 6 is a diagram of a system for delivering nitric oxide.

FIG. 7 is an illustration of a reservoir assembly.

FIG. 8 includes a cut-away of a reservoir assembly and a perspectiveillustration of a reservoir assembly.

FIG. 9 is an illustration of a reservoir assembly.

FIG. 10 is a picture of a metal tube.

FIG. 11 is diagram of a circuit board.

FIG. 12 is a diagram of a system including a disposable module.

FIG. 13 includes perspective drawings of a system including perspectivedrawings of a disposable module and a base unit.

FIG. 14 is a picture of a system in use.

FIG. 15 is a graph of performance data.

FIG. 16 is a graph of ppm NO, NO₂ and NO+NO₂ versus time.

FIG. 17 is a graph of stability of output versus time.

FIG. 18 is a graph of NO and NO₂ output over a period of time.

DETAILED DESCRIPTION

When delivering nitric oxide (NO) for therapeutic use to a mammal, itcan be important to avoid delivery of nitrogen dioxide (NO₂) to themammal. Nitrogen dioxide (NO₂) can be formed by the oxidation of nitricoxide (NO) with oxygen (O₂). The rate of formation of nitrogen dioxide(NO₂) can be proportional to the oxygen (O₂) concentration multiplied bythe square of the nitric oxide (NO) concentration—that is,(O₂)*(NO)*(NO)=NO₂. A NO delivery system can convert nitrogen dioxide(NO₂) to nitric oxide (NO).

Platforms for delivering nitric oxide currently exist. For example, aplatform can be a standalone gas bottle platform, as shown in FIG. 1 . Agas bottle platform 100 can include a gas bottle 105, a gas regulator110 and a GeNO cartridge 115, for example. Using a gas bottle platform,the NO output can be defined by the nitrogen dioxide concentration inthe gas bottle and cannot be varied by the user. For example, if the gasbottle contained 80 ppm of NO₂ in air or oxygen, then the output can be80 ppm of NO₂ in air or oxygen. The gas can be supplied, typically, at apressure of 2000 psi or greater. The output from the gas cylinder can bedelivered to a GeNO cartridge, where one of the O atoms in the NO₂ isstripped out by a reducing agent, for example, ascorbic acid, togenerate ultra pure NO. The GeNO cartridge is described in U.S. patentapplication Ser. No. 12/541,144 and Ser. No. 12/951,811, each of whichis incorporated by reference in its entirety. This platform has beencleared by FDA for use in two clinical trials with human patients. A gasbottle platform can work well, but can be large, heavy and cumbersomebecause the platform can include a heavy aluminum or steel gas pressurecylinder, a gas regulator and a flow controller.

Another variation for delivering NO can be to start with a NO₂ gasconcentration of up to 2,000 ppm in air or oxygen and dilute it down to80 ppm of NO₂. This set up can be even more complex in that it canrequire precision mass flow controllers and meters in order to get astable mixing ratio.

As mentioned above, the disadvantage of the gas bottle platform can bethat the platform can be large and heavy. The platform can also beinconvenient to use for chronic treatment as an ambulatory platform. Gasbottles can also be cumbersome when used in a confined space such as inan Intensive Care Unit, in a hospital or in a home. In addition, the gasbottles need to be tied down to prevent them from falling over andcausing physical injury. Also, the regulator can break off in a fall,and the sudden venting of gas through the opening can cause the heavybottle to become a projectile, which can penetrate numerous walls andcause injury or death.

Examples of commercially available platforms are manufactured by Ikaria,two of which are the INOvent and the INOmax DS. Both of these systemsuse gas bottles of NO diluted in nitrogen (N₂), which is then mixed withoxygen enriched air to provide the inhaled NO gas. Both of these systemsare designed to work with a ventilator in an intensive care setting in ahospital. These platforms are not suitable for ambulatory or home use.

Therefore, there is a need for a nitric oxide delivery platform, whichcan be used in settings where a large, heavy bottle platform isinconvenient, such as an ambulatory or home setting.

As one solution, a system can include a permeation tube or permeationcell to provide the source of NO₂. For example, the NO₂ source can beliquid dinitrogen tetroxide (N₂O₄). This approach has been shown to workwell. This approach has been described in U.S. patent application Ser.No. 12/563,662, which is incorporated by reference in its entirety. N₂O₄can vaporize to produce NO₂, and the process can be reversible. Using apermeation tube, air can be allowed to flow around the permeation tube,where it can mix with the NO₂ that diffuses through the tube, providinga stable mixture of NO₂ in air. The concentration of the NO₂ can becontrolled by a number of factors including, for example, thetemperature of the tube and the volume of the air flow. However, storinga permeation tube can be a problem. For instance, if NO₂ is in contactwith the permeation tube polymer, the storage should be below −11° C. inorder to keep the NO₂ frozen, which can prevent loss of NO₂. Onesolution is to build a separate storage chamber for the permeation tube,which can be connected to the storage tube by a simple valve. Thisdevice can be stored at room temperature without loss of NO₂, and it caneasily be activated by connecting the reservoir to the permeation tube.The combined storage vessel and permeation tube can work well, but itcan have one major disadvantage. Stabilization of a permeation tube cantake a long time when the NO₂ is stored in a reservoir and then suddenlyopened to the permeation tube. The time to stabilize can be severaldays. Pre-saturating the permeation tube with NO₂ first can speed up thestabilization, but this may not work well with long term storage ofmonths or years.

As another solution, a reservoir assembly can be utilized. A reservoirassembly can include a restrictor and a reservoir.

A reservoir can be any compartment or portion of a compartment suitablefor holding N₂O₄, NO₂ or NO, or other compounds which can generate N₂O₄,NO₂ or NO. The reservoir can hold a liquid or a solid, but preferablythe reservoir can hold liquid N₂O₄. The reservoir can be made of anymaterial, which does not react with or adsorb N₂O₄, NO₂ or NO, or othercompounds which can generate N₂O₄, NO₂ or NO. The material should alsobe able to tolerate heat within the appropriate range, discussed below,and repeated heating and cooling.

A reservoir can include a nitrogen dioxide source. A nitrogen dioxidesource can include N₂O₄, NO₂, or compounds which can generate NO₂.Preferably, the nitrogen dioxide source can contain liquid N₂O₄. In thecase of liquid N₂O₄, the amount of liquid N₂O₄ in the reservoir can beless than about 5.0 g, less than about 2.0 g, less than about 1.0 g,less than about 0.50 g, less than 0.25 g or less than 0.10 g; the amountof liquid N₂O₄ in the reservoir can be greater than about 0.05 g,greater than about 0.10 g, greater than about 0.20 g, greater than about0.50 g or greater than about 1.0 g. The amount of liquid N₂O₄ in thereservoir can be less than about 5 ml, less than about 2 ml, less thanabout 1 ml, less than about 0.5 ml, less than about 0.25 ml or less thanabout 0.10 ml; amount of liquid N₂O₄ in the reservoir can be greaterthan about 0.001 ml, greater than about 0.01 ml, greater than about0.05, greater than about 0.10 ml, greater than about 0.25 ml, greaterthan about 0.50 ml or greater than about 1.0 ml.

In one exemplary embodiment, liquid N₂O₄ can be stored in a smallreservoir. For a delivery concentration of 80 parts per million in 1liter of air per minute, for example, the amount of N₂O₄ needed for a 24hour supply can be approximately 0.24 g, or 0.15 ml. N₂O₄ boils at 21°C., so the device should be heated to above this temperature in order tohave a vapor pressure of NO₂ that is greater than atmospheric pressure.Further description may be found in U.S. Provisional Application Nos.61/263,332 and 61/300,425, each of which is herein incorporated byreference in its entirety.

A reservoir can also include nitrogen dioxide vapor or gas in a spaceover the nitrogen dioxide source.

A reservoir can be any size. The size of the reservoir can depend on howthe reservoir will be used. It can also be dependent on the amount ofthe nitrogen dioxide source, the amount of nitrogen dioxide gasrequired, or the length of the time over which a flow of nitrogendioxide would be required. A reservoir can be relatively large, forexample, greater than 1 foot, greater than 2 feet, greater than 5 feet,or greater than 8 feet in height (h₃, FIG. 2 ). A reservoir can also berelatively small, for example, less than 2 feet, less than 1 foot, lessthan 6 inches, less than 4 inches, less than 3 inches, less than 2inches, less than 1 inch, less than 0.5 inch in height (h₃, FIG. 2 ). Anassembly can have a size that can accommodate a reservoir and/oradditional elements, such as a restrictor. An assembly can be relativelylarge, for example, greater than 4 inches, greater than 6 inches orgreater than 1 foot in internal diameter (d₃, FIGS. 2A-B). An assemblycan be relatively small, for example, less than 4 inches, less than 2inches, less than 1 inch, less than 0.75 inch or less than 0.5 inch ininternal diameter (d₃, FIGS. 2A-B).

A restrictor can be any device which can limit the flow of NO₂ from thereservoir. A restrictor can require that there be enough vapour pressureto force the NO₂ vapor out of the reservoir and into the restrictor.

The reservoir can include the restrictor. For example, the restrictorcan be an orifice. The restrictor can be coupled to the reservoir. Forexample, the restrictor can include a tube, most preferably, a capillarytube. The capillary tube can be a quartz capillary tube. The capillarytube can be a narrow bore capillary tube, which can allow for simple,reproducible and accurate use, as well as a cost effective solution. Aconvenient commercially available restrictor can be a narrow bore quartztubing that can be used for gas chromatography (GC).

A restrictor can include a first end and a second end. In someembodiments, the first end of the restrictor can be coupled to areservoir and the second end can be sealed or closed. In someembodiments, the second end, which was previously sealed or closed, canbe opened, unsealed or include a broken seal. In some embodiments, arestrictor can further include a length corresponding to the distancebetween the first end and the second end.

A restrictor can have any dimension, so long as the total pressure dropacross the restrictor can be appropriate for the flow of NO₂ that isrequired. In some embodiments, the length of the restrictor can berelatively long, for example, greater than 4 inches, greater than 6inches, greater than 1 foot, greater than 2 feet, greater than 5 feet,greater than 10 feet or greater than 20 feet long. In some embodiments,a restrictor can be relatively short, for example, at least about 0.1inch, at least about 0.25 inch or at least about 0.5 inch; the lengthcan be at most about 4 inches, at most about 2 inches, at most about 1inch, or at most about 0.5 inch. Preferably, the restrictor can have alength of about 0.75 inch. In some embodiments, the internal diameter ofthe restrictor can be relatively large, for example, greater than about0.100 microns, greater than about 1 microns, greater than about 5microns, greater than about 10 microns, greater than about 50 microns orgreater than about 100 microns. In some embodiments, the internaldiameter of the restrictor can be relatively small, for example, atleast about 0.001, at least about 0.005 microns or at least about 0.010;the internal diameter can be at most about 0.100 microns, at most about0.050 microns, at most about 0.025 microns, or at most about 0.010microns. Preferably, the restrictor can have a diameter of about 0.010microns.

The amount of material (e.g. nitrogen dioxide) that is forced out of thereservoir at any temperature can be dependent upon the diameter of therestriction. Thus, the two key design variables can be the temperatureof the vessel and the diameter and length of the restriction in the topof the vessel. For example, at about 45° C. a tube of 0.010 micronsinternal diameter and 0.75 inches long was used to provide 80 ppm of NO₂in an air stream of 1 l/min.

The restrictor can be made of other materials known to those of skill inthe art. The material should not react with or adsorb N₂O₄, NO₂ or NO,or other compounds which can generate N₂O₄, NO₂ or NO. The materialshould also be able to tolerate heat within the appropriate range,discussed below, and repeated heating and cooling.

A restrictor can be sealed. For example, if the restrictor is made ofquartz or glass, one end of the restrictor can be heat scaled or meltedto close off the opening on that end of the restrictor. The sealed endof the restrictor can be opened by breaking off the end, which canpermit a channel in the restrictor to be fully opened. The restrictorcan be bevelled or scored to allow for an easier and cleaner break. Arestrictor can also be sealed with a metal seal. A metal seal can bemelted, punctured, peeled off or otherwise removed to open the sealedend (i.e. break the seal). A restrictor can include a valve, forexample, a micromachined valve. Other suitable seals and methods forcontrolling or preventing flow are known to those of skill in the art.Once the sealed or closed end is opened, nitrogen dioxide can traversethe length of the restrictor and out the previously closed or sealedend.

A reservoir assembly including a reservoir and a capillary can be lessthan 1 foot, less than 6 inches, less than 5 inches, less than 4 inches,less than 3 inches or less than 2 inches in height (h₁, FIGS. 2A-B). Inan exemplary embodiment, the assembly can be approximately 1.6 inches inheight. An assembly can also be less than 1 inch, less than 0.75 inch orless than 0.5 inch in diameter (d₁, FIGS. 2A-B). In an exemplaryembodiment, the assembly can be approximately 0.4 inch (e.g. 0.43 inch)in diameter.

Referring to FIG. 3 , in one embodiment of a reservoir assembly, arestrictor can be a capillary 320, which can be about 1-inch×10 μminternal diameter (TSP010375 Flexible Fused Silica Capillary TubingPolymicro Technologies). The capillary 320 can be inserted through ametal (303 S.S.) tube 345 made up of two GC nuts 340 and 350 ( 1/16″Stainless Steel Nut Valco P/N ZN1-1.0) connected via their tops to ametal tube 345. Two ferrules 355 (e.g., Graphite Ferrules P/N 202271/16″×0.4 mm Restek) with their flat ends touching can be placed on oneend of the capillary 320, which has the polyamide coating 305 removedbelow the ferrules 355 (e.g., by burning off the polyamide with aflame). The ferrules 355 can hold the capillary 320 securely when thenut 340 is inserted into a separate female end of an adaptor 315, whichcan be itself inserted into the metal (303 S.S.) reservoir 310. Theadaptor 315 can have a metal tube 345 on the reservoir end that cancover and protect the area of the capillary without polyamide.

The end 330 of the capillary 320 opposite the reservoir adaptor can beflame sealed and scored. The sealed capillary can be tested with ahelium flow to assure that the assembly is appropriately sealed and doesnot leak. The reservoir 310 can be filled with liquid NO₂/N₂O₄ bydistillation or other means. The capillary 320 is attached to thereservoir by means of a ⅛ inch pipe thread and sealed. The reservoirassembly can be heated and checked to assure that there are no NO₂leaks.

The entire liquid reservoir assembly can be heated. Methods for heatingthe assembly can include: 1) a hot water bath, 2) a heating mantle thatstraps onto the tubes, insulating the outside of the metal tubing withurethane or another insulator such as paint, and wrapping Kanthalheating wire around the device, and/or 3) using silver paint to paintthe heating element onto top of the insulating paint.

The reservoir assembly 300 can then be attached to the delivery conduitby inserting the sealed end 330 of the capillary 320 with two ferrules355 (Graphite Ferrules P/N 20227 1/16″ X 0.4 mm Restek) with their flatends touching and screwing the exposed GC nut 340 of the reservoirassembly into the delivery conduit.

The sealed end of the capillary 330 can be inserted into an off-centerhole of the internal delivery seal. When ready to use, the internaldelivery seal can be rotated to open the reservoir port, to the systemflow path, which can break the capillary at its scored end 325, thusopening the reservoir to the system flow path and starting the flow ofNO₂.

An advantage of having the capillary tube inside the reservoir andprotected by the tubing can be that the toxic N₂O₄ can only escapethrough the narrow bore quartz tube. In order for any material to escapethe heater has to be turned on to provide the driving force. The tinyliquid reservoir assembly (FIGS. 2A-B), which can measure, for example,about 1.6 inch in height and 0.43 inches in diameter, can replace alarge pressurized gas cylinder, the gas regulator and the gas controlvalve. The size can be similar to that of a cap for a ball point pen.

The assembly can be kept the N₂O₄ frozen solid at dry ice temperatures.However, while this is suitable for laboratory use, it may beimpractical as a safe medical delivery device for use with a patient.

FIG. 4 includes an alternative embodiment that can include a reducednumber of parts, but the overall concept can remain the same. Thisembodiment can be less expensive to produce. The size and shape of thevessel 400 can be such that the liquid 410 can never enter therestrictor 420, e.g. capillary tube. In FIG. 4 , the vessel 400 is onits side, and the liquid 410 level can remain below the level where itcould enter the restrictor 420. Similarly, the vessel 400 can beinverted and it can still function. The restrictor 420 can be protectedby a wider bore splash guard. A baffle (not shown) can also be placed infront of the restrictor 420 so as to eliminate the possibility of aminute droplet entering the restrictor 420.

In another embodiment, methods that are used to seal carbon dioxide inmetal tubes for a wide variety of commercial and consumer applicationscan be used (FIG. 5 ). The liquid NO₂ can be sealed inside a steel oraluminum canister, similar to those used for carbon dioxide (see Lelandcorporation). These devices can have a welded cap made of a thin sheetof steel. The welding can be carried out by resistance heating or othertechniques. The advantage of this system can be that the liquid can besealed inside the container and the containers can be safely shipped.For this application, the volume of the nitrogen dioxide source shouldbe less than 5 ml, less than 2 ml, preferably less than 1 ml.Alternatively, a crimp seal could be used as long as the seal could takethe internal pressure of about 100 psi without leaking. The material canbe aluminum or stainless steel.

The loading and cap penetration technique can be identical to what isused for carbon dioxide pellet guns and for the multitude of other usesof these tiny high pressure cylinders.

In one aspect, a system for delivering nitric oxide can include areservoir, a gas supply and a delivery conduit. A system can furtherinclude a restrictor. A reservoir and a restrictor have been describedabove. In some embodiments, a system can include a reservoir and arestrictor, which are part of a reservoir assembly.

A gas supply can be any suitable source of gas, for example air, oxygenor nitrogen. A preferred gas supply is an air supply, for example, anair pump. For the ambulatory platform an air stream can be provided by asmall air pump. An air compressor, an external supply of air or oxygengas from gas bottles can also be used, including oxygen enriched air fora home oxygen generator. The use of air or oxygen, wet or bone dry, maymake no difference to performance, as measured by a constant output overtime. However, moist air greatly can extend the life of the reducingagent cartridge (e.g. ascorbic acid cartridge) that the NO₂ gas will bepassed through to generate the drug, nitric oxide. Nevertheless, theplatform can be designed for the worst case, which is bone dry air oroxygen.

The system can further include a delivery conduit. A delivery conduitcan include a NO sensor, a NO₂ sensor, or a temperature sensor. A NOsensor can include a chemiluminescent detector or an electrochemicalsensor. A NO₂ sensor can include a chemiluminescent detector or anelectrochemical sensor. A temperature sensor can include a thermistor ora thermometer. In some instances, the system can include a pressuresensor or a flow sensor. A delivery conduit can also include othermedically relevant devices, for example, a filter for eliminatingmicroorganisms prior to inhalation of NO by a patient. It should also beunderstood that a delivery conduit can include additional hardware, suchas tubing and valves, necessary to fluidly communicate gas (e.g. NO₂,NO, air, oxygen, nitrogen, etc.) from one element of the system toanother.

The delivery conduit can have an inlet, which can be coupled to the gassource. The delivery conduit can also include an outlet, which can becouple to a patient interface. A patient interface can include a mouthpiece, nasal cannula, face mask, or fully-sealed face mask.

If the patient required the co-delivery of oxygen, the air feed can bereplaced with oxygen, or a dual lumen cannula can flow both the NO inair and oxygen down parallel lumens to the patient, mixing the NO in airline and the oxygen in the nose.

It is also well within the capability of the technology to add an oxygenconserver to the NO output, thereby extending the life time of thedisposable component.

The second end of a restrictor can also be coupled to the deliveryconduit. The second end of a restrictor can be coupled to the deliveryconduit at a location between the inlet and the outlet of the deliveryconduit. A restrictor can further include a length corresponding to thedistance between the first end and the second end. In some cases, thesecond end of the restrictor is coupled to the delivery conduit suchthat the delivery conduit traverses in a direction perpendicular to thelength of the restrictor.

As the second end of a restrictor can be closed, the delivery conduitcan include a device for opening the second end or breaking the seal onthe second end.

A system can further include a GeNO cartridge. The cartridge can employa surface-active material coated with an aqueous solution of a reducingagent, for example an antioxidant, as a simple and effective mechanismfor making the conversion. More particularly, NO₂ can be converted to NOby passing the dilute gaseous NO₂ over a surface-active material coatedwith an aqueous solution of a reducing agent, e.g. an antioxidant. As anexample, when the aqueous antioxidant is ascorbic acid (that is, vitaminC), the reaction can be quantitative at ambient temperatures.

One example of a surface-active material can be silica gel. Anotherexample of a surface-active material that can be used is cotton. Thesurface-active material may be or may include a substrate capable ofretaining a liquid, for example, water. Another type of surface-activematerial that has a large surface area that is capable of absorbingmoisture also may be used.

FIG. 6 illustrates a cartridge 600 for generating NO by converting NO₂to NO. The cartridge 600, which may be referred to as a cartridge, aconverter, a NO generation cartridge, a GENO cartridge, a GENO cylinder,GENO converter or Nitrosy™ Primary Cartridge, can include an inlet 605and an outlet 610. Screen and/or glass wool 615 can be located at theinlet 605 and/or the outlet 610. The remainder of the cartridge 600 canbe filled with a surface-active material 620 that is soaked with asaturated solution including a reducing agent to coat the surface-activematerial. The saturated solution can be, for example, an antioxidant inwater. The screen and/or glass wool 615 can also be soaked with thesaturated solution before being inserted into the cartridge 600. Theantioxidant can be ascorbic acid.

In a general process for converting NO₂ to NO, a gas flow (e.g. airflow) having NO₂ can be received through the inlet 605. The gas flow canbe fluidly communicated to the outlet 610 through the surface-activematerial 620 coated with the aqueous reducing agent, e.g. antioxidant.As long as the surface-active material 620 remains moist and thereducing agent may not been used up in the conversion, the generalprocess can be effective at converting NO₂ to NO at ambient temperature.

The inlet 605 also may receive the air flow having NO₂, for example,from source of NO₂. A source of NO₂ can include a pressurized bottle ofNO₂, which also may be referred to as a tank of NO₂. The inlet 605 alsomay receive a gas flow with NO₂ in nitrogen, air, or oxygen. Theconversion can occur over a wide concentration range. Experiments havebeen carried out at concentrations in a gas including from about 2 ppmNO₂ to 100 ppm NO₂, and even to over 1000 ppm NO₂. In one example, acartridge that was approximately 6 inches long and had a diameter of1.5-inches was packed with silica gel that had first been soaked in asaturated aqueous solution of ascorbic acid. The moist silica gel wasprepared using ascorbic acid (i.e., vitamin C) designated as A.C.Sreagent grade 99.1% pure from Aldrich Chemical Company and silica gelfrom Fischer Scientific International, Inc., designated as S8 32-1, 40of Grade of 35 to 70 sized mesh. Other sizes of silica gel also can beeffective. For example, silica gel having an eighth-inch diameter couldalso work.

The silica gel can be moistened with a saturated solution including areducing agent. For example, a saturated solution of ascorbic acid inwater; more specifically, the saturated solution can be a saturatedsolution that had been prepared by mixing 35% by weight ascorbic acid inwater, stirring, and straining the water/ascorbic acid mixture throughthe silica gel, followed by draining. The conversion of NO₂ to NO canproceed well when the silica gel coated with ascorbic acid is moist. Theconversion of NO₂ to NO may not proceed well in an aqueous solution ofascorbic acid alone.

The cartridge can be filled with the wet silica gel/reducing agent. Forexample, a cartridge filled with the wet silica gel/ascorbic acid wasable to convert 1000 ppm of NO₂ in air to NO at a flow rate of 150 mlper minute, quantitatively, non-stop for over 12 days. A wide variety offlow rates and NO₂ concentrations have been successfully tested, rangingfrom only a few ml per minute to flow rates of up to 5,000 ml perminute. Any appropriate reducing agent that can convert NO₂ or N₂O₄ toNO can be used as determined by a person of skill in the art. Forexample, the reducing agent can include a hydroquinone, glutathione,and/or one or more reduced metal salts such as Fe(II), Mo(VI), NaI,Ti(III) or Cr(III), thiols, or NO₂ ⁻. The reducing agent can be anantioxidant. The antioxidant can be an aqueous solution of anantioxidant. The antioxidant can be ascorbic acid, alpha tocopherol, orgamma tocopherol. Any appropriate antioxidant can be used depending onthe activities and properties as determined by a person of skill in theart. The antioxidant can be used dry or wet.

The antioxidant/surface-active material GENO cartridge may be used forinhalation therapy. In one such example, the GENO cartridge can be usedas a NO₂ scrubber for NO inhalation therapy that delivers NO from apressurized bottle source. The GENO cartridge can be used to remove anyNO₂ that chemically forms during inhalation therapy. This GENO cartridgecan be used to help ensure that no harmful levels of NO₂ areinadvertently inhaled by the patient.

Using the system as an inhaled NO drug delivery device, the NO₂ outputin air or oxygen can be passed through a GeNO cartridge, which stripsout one of the O atoms from the NO₂ to produce ultra pure NO.

Referring to FIG. 7 , the cartridges 700 can be blow molded withinternal ridges 705 and valleys 710. When packed with the surface activematerial and reducing agent (e.g. silica gel/ascorbic acid powder), theparticles can tend to pack, leaving a small air gap at the top. If thecartridge was allowed to be vibrated on its side, the material couldsettle. If the tube had a smooth bore, the space above the powder couldcreate a path that bypassed the GeNO converter. By having the ridges 705and valleys 710, the powder can settle and the vapour cannot have apathway that would bypass the chemistry reactor. The height of the ridgeand its width can be determined by calculation and then confirmedexperimentally.

The cap for the cartridges can be molded from plastic (FIG. 8 ).

An exemplary embodiment of a system is shown in FIG. 9 . Referring toFIG. 9 , a system 900 can include a reservoir 905. A reservoir 905 caninclude a nitrogen dioxide source 910, for example, liquid N₂O₄. Overthe nitrogen dioxide source can be nitrogen dioxide vapor 915. As thevapor pressure of the nitrogen dioxide vapor 915 is increased, forexample by heating the nitrogen dioxide, the nitrogen dioxide vapor 915can be forced into a restrictor 920. The restrictor 920 can be coupledto the reservoir at a first end 925. The second end 930 of therestrictor can be closed or sealed for storage. To use the system, thesecond end 930 of the restrictor can be opened or the seal can bebroken, which can allow nitrogen dioxide to traverse the length of therestrictor 920 and out the second end 930 of the restrictor. A gassupply 935 can provide gas 950, which can traverse through a deliveryconduit 940. An inlet 945 of the delivery conduit 940 can be coupled tothe gas supply 935. The second end 930 of the restrictor can also becoupled to the delivery conduit 940. In that way, as gas 950 from thegas supply 935 traverses through the delivery conduit 940 and past thesecond end 930 of the restrictor, the gas 950 from the gas supply 935and the nitrogen dioxide vapor 915 from the reservoir will mix, forminga nitrogen dioxide-gas mixture 955. The nitrogen dioxide-gas mixture canthen pass through a number of devices including, but not limited to,sensors, cartridges or filters, as discussed below.

Another exemplary embodiment of a system is shown in FIG. 10 . Referringto FIG. 10 , a system 1000 can include a reservoir 1005, which caninclude a nitrogen dioxide source 1010, for example, liquid N₂O₄. Overthe nitrogen dioxide source can be nitrogen dioxide vapor 1015. As thevapor pressure of the nitrogen dioxide vapor 1015 is increased, forexample by heating the nitrogen dioxide, the nitrogen dioxide vapor 1015can be forced into a restrictor 1020. The restrictor 1020 can be coupledto the reservoir 1005 at a first end of the restrictor 1025. The secondend 1030 of the restrictor can be closed or sealed for storage. To usethe system, the second end 1030 can be opened or the seal can be broken,which can allow nitrogen dioxide to traverse the length of therestrictor 1020 and out the second end 1030. A gas supply 1035 canprovide gas 1050, which can traverse through a delivery conduit 1040. Aninlet 1045 of the delivery conduit 1040 can be coupled to the gas supply1035. The second end 1030 of the restrictor can also be coupled to thedelivery conduit 1040. In that way, as gas 1050 from the gas supply 1035traverses through the delivery conduit 1040 and over the second end 1030of the restrictor, the gas 1050 from the gas supply 1035 and thenitrogen dioxide vapor 1015 from the reservoir will mix, forming anitrogen dioxide-gas mixture 1055. The nitrogen dioxide-gas mixture 1055can then pass through a first cartridge 1060 included in the deliveryconduit. Prior to or following the first cartridge 1060, the nitrogendioxide-gas mixture 1055 can pass through a number of devices which canbe included the delivery conduit including, but not limited to, sensorsor filters, as discussed in more detail below. The nitrogen dioxide-gasmixture 1055 can also pass through a second cartridge 1070 prior toexiting the delivery conduit. A patient interface can be coupled to anoutlet 1065 of the delivery conduit.

A system can include a heating element. A heating element can be anydevice that can alter and maintain the temperature of the system, or atleast the reservoir and/or the restrictor. The heating element can be ahot water bath, a heating mantle or heating wire. Insulated heatingwires can be wrapped directly onto the tube surface. A heated well canalso be used. Other suitable examples of a heating element are known tothose of skill in the art.

In an exemplary embodiment, the system or a portion of the system, forexample the reservoir and/or restrictor, can be heated by means of asimple flexible circuit board with the wires etched onto the surface(FIG. 11 ). A device including a thermistor can be built into thecircuit for measuring and controlling the temperature.

When heating a system or a portion of a system, the lowest temperaturethat is practical can be about 25° C. However, it can be difficult tocontrol the temperature precisely when it is close to ambienttemperature. For maximum control, the temperature should be set to beabove the highest possible ambient temperatures. The upper temperaturelimit can, in principle, be many hundreds of degrees centigrade. Apractical limit can be the engineering balance of (a) having the liquidhot enough to develop the pressure that can force the vapor out of thedevice, and (b) minimizing the amount of energy that may be needed,especially for battery powered devices, minimizing the amount of thermalinsulation that may be needed (a size factor) and the complexity of thestorage vessel as far as ensuring that it can withstand the pressuresthat may be developed inside the vessel. The temperature can be at leastabout 25° C., at least about 30° C., at least about 35° C., at leastabout 40° C., at least about 45° C. or at least about 50° C.; thetemperature can be at most about 200° C., at most about 150° C., at mostabout 100° C., or at most about 75° C. The optimum temperature range canbe about 45 to 75° C., which can develop enough vapor pressure to forcethe NO₂ vapor through the restrictor.

The reservoir and/or the restrictor can be heated. The reservoir and therestrictor can be heated to substantially the same temperatures, forexample less than 10° C. difference, less than 5° C. difference, 2° C.difference or less than 1° C. difference between the temperature of thereservoir and the temperature of the restrictor. This can avoidcondensation of NO₂. Also, the temperature of the system, morespecifically, the reservoir and/or the restrictor, can be controlled tobetter than about 1° C., preferably better than about 0.5° C., in orderto maintain a constant output of NO₂ vapor. The higher the temperatureof the vessel, the better the temperature control should be. This needcan come about because the vapor pressure can approximately double witha 10 degree rise in temperature. Thus, for a fixed restrictor and fixedair flow, the concentration of NO₂ in the output can double fromapproximately 40 ppm at 45° C. to 80 ppm at 55° C., to 160 ppm at 65° C.to 320 ppm at 75° C. At 65° C., a 0.5° C. variation in temperature cancause a change in output that is more than 4 times greater than at 45°C.

In one embodiment, a portion of the system can be reusable and a portionof the system can be disposable. For example, a reusable base unit caninclude a gas supply (e.g. air pump). A reusable base unit can alsoinclude sensors, power supply (e.g. batteries), alarm systems, lights,indicators, and/or electronics (FIG. 12 ). A disposable unit can includereservoir, the nitrogen dioxide source (e.g. N₂O₄ storage vessel),restrictor and/or at least one GeNO cartridge (e.g. two GeNOcartridges). The disposable unit can further include filters, a heatingelement, and/or sensors. One purpose of the design can be to make thedisposable system as low cost as possible, while ensuring safety. Theliquid N₂O₄ source and the at least one GeNO cartridge can be containedin a sealed unit that can be produced in large quantities. A typicalpatient can use one disposable unit per day, which can depend upon thesize of the reservoir, the amount of the nitrogen dioxide source, thesize of the cartridges, and the dose required.

In one embodiment, between the two cartridges, the flow path can passover an NO sensor (P/N NO-D4 Alphasense, Ltd. United Kingdom), which canverify that the NO levels do not exceed or fall below specified levels.If necessary, the sensor can trigger alarms or shut off the gas supply.One embodiment is shown below in FIG. 13 , which shows the base and thedisposable, separately and combined.

Some of the safety features of the disposable/reusable system caninclude the following: 1) an activated charcoal filter on the air intakeprior to the valve which breaks off the quartz tip, where the charcoalfilter could be large enough to adsorb all of the NO₂ in the reservoir;2) a tip enclosed in a sealed Teflon chamber during shipment, which canonly be moved by inserting the disposable unit into the base unit, sothat even if the glass tip broke the NO₂ would be contained; 3) aninterlock so that the disposable unit can only be used once; 4) warningsand alarms, including, but not limited to, warning lights for lowbattery, low or high NO, wrong flow, etc.; 5) an encased liquidreservoir, where the reservoir can be entirely encased in an activatedcharcoal sheath which will be of sufficient mass to adsorb all of theNO₂ in the storage vessel; 6) a thermal fuse on the heater element sothat the unit can never exceed its set temperature; and 7) sensors forflow, pressure atmospheric pressure, etc.

FIG. 14 shows the size of an exemplary device, in which a man is shownwearing the device while fishing. The miniaturization can be animportant feature. Current commercially available delivery systems forinhaled NO can require a patient to be confined to a bed in a hospitaland usually in an Intensive Care Unit. The ability to supply inhaled NOchronically in a simple fashion represents a breakthrough in treatmentwith inhaled NO.

A system can be relatively small. The system can weigh less than 64ounces, less than 32 ounces or less than 16 ounces. The system can beless than 2 feet, less than 1.5 feet, less than 1 foot in height. Thesystem can be less than 2 feet, less than 1.5 feet, less than 1 foot,less than 9 inches or less than 6 inches in width. The system can beless than 6 inches, less than 4 inches, less than 3 inches or less than2 inches in depth.

A method of for delivering nitric oxide can include breaking the seal ona second end or opening a closed second end of a restrictor. Therestrictor can have a first end in a reservoir containing a nitrogendioxide source. The method can also include heating the reservoir andthe restrictor, which can also heat the nitrogen dioxide source in thereservoir and nitrogen dioxide gas in the reservoir and/or therestrictor. As the nitrogen dioxide gas is heated, vapor pressure canaccumulate within the reservoir, releasing the nitrogen dioxide gas intothe restrictor. Once the second end is opened or unsealed, nitrogendioxide gas that is forced into the restrictor can pass through thesecond end of the restrictor. The method can further include passing agas from a gas supply across a second end of a restrictor. Passing gasfrom a gas supply across the second end of a restrictor can createnegative pressure at the second end of the restrictor. The increasedvapor pressure in the reservoir and/or the negative pressure at thesecond end of the restrictor can three NO₂ vapor through the restrictor.This can result in the NO₂ gas mixing with the gas from the gas supply.The NO₂ gas mixed with the gas from the gas supply can then be passedthrough at least one GeNO converter. Additionally, a method can includemonitoring the level of NO with a NO sensor, monitoring the level of NO₂with a NO₂ sensor, or monitoring the temperature with a temperaturesensor.

In one example, the system is activated by breaking the seal of a sealedrestrictor, for example, breaking off the tip of a quartz capillaryrestrictor tube. NO₂ vapor can be expelled from the reservoir at aconstant flow rate, which can be dependent on the availability of liquidin the reservoir and the temperature of the reservoir. The NO₂ vapor canmix with gas, e.g. air, from a small pump and the dilute NO₂ mixture canthen be allowed to pass through a first GeNO converter, where the NO,can be converted into NO. The converter can be made up of fine silicagel soaked in a reducing agent, e.g. ascorbic acid solution, and thenpartially dried. The NO in gas stream can be flowed to the second GeNOconverter. A second GeNO converter can provide double redundancy. Eachof the two cartridges can have sufficient silica gel-ascorbic acidpowder to convert 1.5 times the content of the liquid in the reservoir.Also, each cartridge can be manufactured from a different lot. The NO ingas stream can be passed across an optional NO, an optional NO₂electrochemical sensor, an optional pressure and/or optional flowsensor. The NO vapor in air can then be delivered to a patient by meansof a nasal cannula.

For home use, patients can use a system that delivers a fixed output perunit time. A patient needing a high dose can be provided with a modifiedsystem in which increased output can be achieved either by increasingthe temperature of the reservoir, changing the diameter of therestrictor or length of the restrictor.

In a hospital setting, the nurse may have a need to vary both the flowrate of air and the gas concentration. This can be accomplished byvarying the temperature of the reservoir for increase the output of thereservoir. The air flow can be adjusted, either from a compressor orfrom increasing the power of a small built in air pump. A system withvariable flow and variable output can include a monitor and display ofthe flow rate and the NO concentration.

EXAMPLES Example 1

The slope of the plot of log (NO) versus 1/T, where T is the absolutetemperature, should be a straight line. A typical plot obtained using anitric oxide delivery system is shown in FIG. 15 . The small variationfrom linearity may due to experimental error due primarily to inadequatetemperature control. The flow rate was 1 liter per minute of air.

Example 2

The nitric oxide delivery systems can be operated for many days on endwithout significant variation or degradation. For example, a typicalplot of ppm NO, NO₂ and NO+NO₂ versus time is shown in FIG. 16 for oneexperiment over a period of about 36 hours. In this experiment the NO₂to NO conversion cartridge was absent. It shows the output of thereservoir, showing the NO level (green line), the NO₂ level (yellowline) and the NO+NO₂ response (black line) with time in minutes. Withoutbeing held to any theory, the initial spike was likely due to theapproximately 1% NO impurity that is sometimes added to N₂O₄ to reducecorrosion cracking during its conventional use as a rocket fueloxidiser. Because it has a higher vapor pressure, the NO will de-gasfrom the liquid in the early stages oxidiser.

Example 3

FIG. 17 shows the output when the NO conversion cartridges were includedin the system to convert the NO₂. In this experiment, the data wascollected for 780 minutes (13 hours). While the data shows some drift,it was well within the ±20% that is required for clinical use.

Example 4

FIG. 18 shows the NO and NO₂ output for a period of 24 hours. The NO₂concentration after the gas flow was passed through the cartridges wasessentially zero.

The various embodiments described above are provided by way ofillustration only and should not be construed to limit the claimedinvention. Those skilled in the art will readily recognize variousmodifications and changes that may be made to the claimed inventionwithout following the example embodiments and applications illustratedand described herein, and without departing from the true spirit andscope of the claimed invention, which is set forth in the followingclaims.

What is claimed:
 1. A method, comprising: heating a reservoir containingdinitrogen tetroxide, the reservoir coupled to a first end of arestrictor, a second end of the restrictor being sealable; opening thesecond end of the restrictor; releasing nitrogen dioxide from thereservoir via the restrictor into a delivery conduit; flowing a gas froma gas supply into the delivery conduit to cause the gas from the gassupply and the nitrogen dioxide to form a gas mixture in the deliveryconduit; converting the nitrogen dioxide to nitric oxide by flowing thegas mixture through at least one cartridge that includes asurface-activated material and a reducing agent; and delivering nitricoxide from an outlet of the delivery conduit.
 2. The method of claim 1,wherein the restrictor includes a capillary tube.
 3. The method of claim1, wherein the restrictor includes a valve configured to selectivelyopen the second end of the restrictor.
 4. The method of claim 3, furthercomprising flowing the gas mixture through at least one of a nitricoxide sensor, a nitrogen dioxide sensor, a flow sensor, a temperaturesensor, or a pressure sensor.
 5. An apparatus comprising: a gas supply;a reservoir containing dinitrogen tetroxide; a heating elementconfigured to heat the reservoir; a restrictor, including a first end ofthe restrictor coupled to the reservoir and a second end of therestrictor being sealable; and a delivery conduit coupled to therestrictor and configured to deliver nitric oxide, the delivery conduitincluding (1) an inlet coupled to the gas supply and configured toreceive nitrogen dioxide, (2) a cartridge including a surface-activatedmaterial and a reducing agent, the cartridge configured to convertnitrogen dioxide to nitric oxide, and (3) an outlet configured todeliver nitric oxide.
 6. The apparatus of claim 5, wherein therestrictor is a capillary tube.
 7. The apparatus of claim 6, wherein therestrictor is made of quartz or glass.
 8. The apparatus of claim 6,wherein the restrictor is beveled or scored to allow the opening of thesecond end sealed.
 9. The apparatus of claim 6, wherein the gas supplyis an air pump.
 10. The apparatus of claim 5, wherein the restrictorincludes a valve configured to open the second end.
 11. The apparatus ofclaim 5, wherein the gas supply is an air supply.
 12. The apparatus ofclaim 5, wherein the delivery conduit includes at least one of a nitricoxide sensor, a nitrogen dioxide sensor, a flow sensor, a temperaturesensor, a pressure sensor, or a sensor for atmospheric pressure.
 13. Theapparatus of claim 5, wherein the reservoir, the restrictor, and thecartridge form a disposable module capable of being removed from theapparatus.
 14. The apparatus of claim 5, wherein the outlet is coupledto a patient interface.
 15. An apparatus comprising: a gas supply; arestrictor having a second end that is sealable; a reservoir includingdinitrogen tetroxide, the reservoir coupled to a first end of therestrictor; a heating element; a circuit board configured to adjust atemperature of the reservoir using the heating element; and a deliveryconduit coupled to a second end of the restrictor and configured todeliver nitric oxide, the delivery conduit including (1) an inletcoupled to the gas supply and configured to receive nitrogen dioxide,(2) a cartridge including a surface-activated material and a reducingagent, the cartridge configured to convert nitrogen dioxide to nitricoxide, and (3) an outlet configured to deliver nitric oxide.
 16. Theapparatus of claim 15, wherein the circuit board includes a thermistorconfigured to measure the temperature of the reservoir.
 17. Theapparatus of claim 15, wherein increasing the temperature of thereservoir assembly is configured to increase a concentration of nitricoxide delivered via the delivery conduit.